Amphetamine and the amphetamine derivative 3, 4-methylenedioxymethamphetamine (MDMA) are two widely abused drugs which bind to and reverse monoamine transporters, causing efflux of monoamines into the synapse. Despite their mechanistic similarities, the use profile and effects of these drugs vary. Amphetamine acts primarily on the dopamine transporter and is behaviorally characterized by compulsive use. The proposed experiments will allow analysis of amphetamine regulation of dopamine efflux through identification of gene expression changes during phases of amphetamine self-administration, abstinence, and reinstatement. Conversely, MDMA preferentially reverses serotonin transport, which results in feelings of well being, but is linked to persistent serotonergic deficits and long-lasting changes in memory and cognition. Changes in behavioral measures of memory after MDMA self-administration will be examined, and the alterations in gene expression that may underlie these changes will be analyzed by microarrays. In summary, the proposed studies will allow investigation of transcriptional responses to monoamine reuptake reversal in behaviorally relevant settings.